Antibiotic A204I Derivatives

ABSTRACT

Antibiotic A204I monoether and monothioether derivatives are anticoccidial, as well as antimicrobial agents. Some A204I monoether derivatives are also insecticidal and acaricidal agents and increase feed-utilization efficiency in ruminants.

United States Patent [191 Hamill [451 Sept. 23, 1975 [54] ANTIBlOTlC A2041 DERIVATIVES [75] Inventor: Robert L. Hamill, New Ross, Ind.

[73] Assignee: Eli Lilly and Company, Indianapolis,

Ind.

[22] Filed: Nov. 15, 1974 [21] Appl. N0.: 524,178

[52] U.S. Cl 260/345.7; 424/283 [51] Int. Cl. C071) 309/22 [58] Field of Search 260/3457, 345.1

[56] References Cited UNITED STATES PATENTS 3,705,238 l2/l972 Hamill et al. 424/283 OTHER PUBLICATIONS Jones et al., J. Amer. Chem. Soc., 95, 3399, (1973).

Primary ExaniinerBernard Helfin Assistant ExaminerNicky Chan Attorney, Agem, or FirmNancy J. Harrison; Everet F. Smith [5 7] I ABSTRACT Antibiotic A2041 monoether and monothioether derivatives are anticoccidial, as well as antimicrobial agents. Som'e A204l monoether derivatives are also insecticidal and acaricidal agents and increase feedutilization efficiency in ruminants.

4 Claims, N0 Drawings ANTIBIOTIC A2041 DERIVATIVES BACKGROUND OF THE INVENTION 1. Field of the Invention Coccidiosis is a well-known protozoan disease resulting from infection by one or more species of Eimeria or Isospora (for a summary, see Lund and Farr in Diseases of Poultry, FIfth Ed. Biester and Schwarte, Eds, Iowa State University Press, Ames, Ia., 1965, pp. l056-l 096 When left untreated, the severe infections of coccidiosis lead to poor weight gain, reduced feed efficiency, high morbidity and mortality in fowl. The morbidity and mortality caused by coccidiosis infections create extensive economic loss when such infec tions are left untreated or unchecked. The control of this disease is, therefore, of paramount importance to the poultry industry. In the continuing efforts to find improved agents for the control of this disease, decreased toxicity is one of the desirable improvements.

2. Description of Prior Art Antibiotic A204 factor I, from which the novel compounds of the present invention are prepared, is described in US. Pat. No. 3,705,238. The structure of antibiotic A2041 has been determined by X-ray diffraction studies [Noel D. Jones, Michael O. Chaney, James W. Chamberlin, Robert L. Hamill and Sue Chen, J. Amer. Chem. Soc. 95, 3399-3400 (1973)]. This structure is shown in Formula I:

MeO

MeO Me Me OMe SUMMARY OF THE INVENTION This invention relates to novel monoether and monothioether derivatives of antibiotic A2041. In particular, 50 sitions WhlCh contain an A2041 derivative and which,

it relates to antibiotic A2041 ether and thioether derivatives of the following formula:

MeO

wherein:

R represents C -Cg-alkyl, C C -alkoxy, or hydroxy',

m represents 0-2; and

n represents O-3;

and to the physiologically-acceptable cationic salts thereof. For the sake of brevity, the expression A204I derivative as used herein refers to an A204I derivative as herein defined.

The novel A204I derivatives of the present invention are antimicrobial agents. In a preferred application of the compounds of this invention, the A204] derivatives are effective anticoccidial agents. The A2041 derivatives of the present invention are less toxic than antibiotic A2041. This invention also relates to novel compowhen added to animal feedstuffs, are effective anticoccidial agents. Many of the A204! derivatives also ex- 3 hibit acaricidal and insecticidal activity and, additionally, increase feed-utilization efficiency in ruminants.

DETAILED DESCRlPTlONOF THE INVENTION dl'0Xy-C C a1ky1 moiety or, when Y is 0,..to the 2,3-dihydroxyprop-l-yl moiety.

The term haloalkyl refers to a C C -alkyl moiety having from one to three halogen substituents, selected from the group consisting of bro mine, chlorine, and fluorine. When the alkyl moiety is dihaloor trihalosubstituted, the halo-substituents must be the same halogen moiety. i

Physiologically-acceptable cationic salts are those salts formed from cations, which do' not increasethe toxicity of the compound as a wholetoward warm: blooded animals. Otherwise, the identity of the saltforming cation is not critical, although in some instances one may be chosen which exhibits special advantage s,'such as solubility, ease of crystallization and the like. Representative and suitable cations include the alkali metals such ajs sodi'umf potassium and lithiufm; alkaline-earth metals such as calcium, magnesium and strontium; heavy metals such as copper and zinc; ammonium; and the like.

Preferred A2041 derivatives are those compounds of Formula 11 wherein Y represents 0 and R represents C,C -alkyl. These preferred derivatives are prepared by reaction of A2041 with alcohols which are, in general, more readily available and less expensive than the starting alcohols or thiols used in the preparation of "'zene, ether,tetrahydrofuran or dioxane may be added to facilitate'the reaction. Reactions generally occurat 'r oomtemperature, although higher temperatures may be used.

Although ordinary reaction work-up procedures are sometimes sufficient, additional purification may be required to obtain the compounds of this invention. Such purification may be accomplished by well-known methods, such as, for example, column chromatography, thin-layer chromatography, fractional crystallization and the like. Illustrative suitable adsorbents for chromatographic separations include silica gel, alumina,

Florisil (magnesium silicatefFloridin Co.,-P. O. Box

989, Tallahassee, Fla. carbon,'and ion exchange resins.

The A2041 derivatives are useful anticoccidial agents. More particularly, when administered to poultry, the A2041 derivatives are effective agents in the prophylactic treatment for and in the control of coccid- 4 iosis. Th e A 2 041 derivativegis, conveniently administered to poultry as a feed component.

In a preferred embodiment, novel compositions are provided which comprise .an. A2041 derivative intimately'dispersed in or-admixed with an edible, inert, solid carrier or diluent to provide a premix or medicated feed supplement. An in'ert carrier or diluent is one that is nonreactive with respect to the A2041 derivative. The carrier or diluent is preferably one that is or maybe an ingredient of animal feed.

The preferred compositions of this invention are feed premixes in which an A2041 derivative is present in relatively large amounts. These compositions are suitable for-addition to poultry feed either. directly or after an intermediate dilution or blending step. Examples of carriers or diluents suitable for such compositions are animal-feed ingredients such as distillers dried grains,

soybean mill run, alfalfa granules, wheat middlings,

corn gluten meal, exfoliated hydrobiotites, corn meal, citrus meal, fermentation residues, ground oyster shells, attapulgus clay, wheat shorts, molasses solubles, corncob meal, edible vegetable substances, toasted dehulled soya flour,'soybean feed, soybean meal feed antibiotic mycelia, soya grits, kaolin, talc, crushed limestone,.an d,the like.f-';l'he preferred diluents are soybean products such as soybean mill run and soybean feed, alfalfa products such as alfalfa granules, and corn products such as corn gluten meal and corn grits.

The compositions are prepared by intimately dispersing or admixing an A2041 derivative throughout the solid inert carrier by methods such as grinding, stirring, milling, or tumbling. In some instances, the A2041 derivative may be adsorbed on the carrier by spraying a solution thereof into a rotating mill containing the diluent. By selecting proper diluents and by altering the j ratio of carrierto active ingredient, compositions of any desiredconcentration can be prepared.

Thefee'd premixes are formulated so that the total active ingredient is present within the range of from 5 to percent by weight, and the diluent or carrier is present correspondingly within the range of from to 20 percent by weight of the premix. A preferred ratio is about 40 percent by weight of A2041 derivative to about 60 percent by weight of diluent. The premixes may be further diluted with an animal-feed supplement or may be added directly to an animal feedstuff in order to provide a suitable medicated feedstuff which can be eaten directly by poultry. w v

The premix diluted with feed supplement may be further dilutedwith rnaterialssuch as corn meal or soybean meal before being incorporated in the animal feed. This dilution can serveto facilitate uniform distribution of the anticoccidial agents in the finished feed. The finished feed is one that contains a source of fat, protein, carbohydrate, minerals, vitamins and other nutritional factors.

When used in the prophylactic treatment for coccidiosis, relatively low levels of an A2041 derivative in poultry feed are sufficient to afford poultry good protection against coccidiosis. For example, a nontoxic amount of an A2041 derivative is administered to chickens, preferably orally on a daily basis, in an amount of from-about 0.001 to about 0.05 percent of the daily feed intake by weight and preferably in the range of from 0.0025 to 0.01 percent. The most advantageous dosage level will, of course, vary with particular circumstances, such as the type and severity of the coccidial infection to be treated, the daily feed intake of the birds, and the like.

Prior to administration of the medicated feed to poultry, the premix is uniformly dispersed in the animal feed by suitable mixing or blending procedures.

In treating poultry according to the method of this invention, one-day-old broiler cockerels are started on the medicated feed containing an A2041 derivative. This procedure applies for broilers, roasters, fryers, and for replacement stock for layer or broiler-breeder flocks. Broiler birds are maintained on the medicated feed of this invention throughout their life. Replacement stock for layer flocks are maintained on this medicated feed for a minimum of 14 to 22 weeks.

Alternatively, an A2041 derivative or a salt thereof is added directly to a conventional basal ration which can comprise the following ingredients: meat and bone scrap; fishmeal; vitamin B poultry-byproduct meal; dehulled-soybean-oil meal; dehydrated alfalfa meal; corn gluten meal; pulverized oats; ground barley; corn meal; wheat middlings; dried grain and whey fermentation solubles; methionine hydroxy analog calcium; riboflavin; calcium pantothenate; choline chloride; niacin; animal fat; menadione sodium bisulfite; vitamin E supplement; butylated hydroxytoluene; vitamin A palmitate; deactivated animal sterol; calcium carbonate; defluorinated phosphate; sodium chloride; calcium iodate; manganese oxide; zinc oxide; cobalt hydroxide; and cobalt carbonate.

Such medicated feed composition is prepared by adding the A2041 derivative to the basal ration in an amount constituting from about 0.001 to about 0.05 percent by weight of the final mixture. The ingredients are thoroughly admixed to provide the ration which is fed to young chicks.

The anticoccidial effects of the A2041 derivatives are illustrated by the effects of various of the compounds in controlling single-species infections of Eimeria tenella, Eirileria rzecatrix, Eimeria mivati, and Eimeria brunetti arid a multiple-species infection of Eimeria maxima and Eimeria tenella in chickens.

M ETHOD For these studies, groups of five 7-day-0ld chicks were fed a mash diet containing therein a uniformly dispersed A2041 derivative. After having been on this ration for 48 hours, each bird was inoculated with sporulated oocysts of the particular species of Eimeria being tested.

Other groups of five 7-day-old chickens were fed a mash diet which did not contain an A2041 derivative. Some of these groups were also inoculated with Eimeria after 48 hours and served as infected controls. Other of these groups were not inoculated with Eimeria and served as normal controls. The results of treatment were evaluated seven days after inoculation. The birds were weighed, sacrificed and examined for evidence of coccidial lesions. Coccidial involvement was expressed on an arbitrary scale, increasing from zero (no evidence of coccidiosis) to four (maximum involvement for the Eimeria sp. tested). The percent reduction in lesion score is calculated by subtracting the average lesion score of the treated group from the average lesion score of the infected control group, dividing this difference by the average lesion score of the infected control group, and multiplying the quotient by 100.

The percent weight gain is calculated using the weight gain of normal controls as 100 percent.

The results of these tests are shown in the following tables:

TABLE 1 Efficacy of A2041 Derivatives Against E. lenella in Broiler Cockcrels Average 7: 7: 7c Cecal Reduction A2041 7: Mortal- Weight Lesion Lesion Ether in Diet ity Gain Score Score Methyl .005 0 98 .1 98

.001 65 l 5 95 3 .7 Ethyl .005 S 95 .2 95 .00165 0 88 2.4 40 n-Propyl .0066 20 79 3 .7 0 .00165 35 79 4.0 0 Infected 45 83 4.0 Controls Normal 100 Controls n'Propyl .005 0 96 0 100 .002 5 0 8 7 1 .8 5 0 Isopropyl .0025 0 95 2.3 40 Methyl .0025 0 2.9 40 cellosolve Infected 5 55 3 .6 control Three replicates (If five birds each per medicated group; four replicates of five birds each per infected-control group. -Due to coccidiosis.

TABLE I1 Efficacy of A2041 Derivatives Against E. necmrix in Broiler Cockcrels 7: Average 7r Re 7: Mor- 7: Intestinal duction A2041 in tal- Weight Lesion Lesion Ether Diet ity Gain Score Score n-Propyl .01 0 89 0 100 .005 6.7 92 0.2 95 .0025 0 63 1.6 59 Methyl .02 6.7 95 0.67 83 .01 26.7 49 2.5 35

Infected 85 18 3.9 Controls Normal Controls Three replical es of five birds each per medicated group; four replicates of five birds each per infected control group -Due to coccidiosis.

TABLE III Efficacy of A2041 Derivatives Against E. mirari in Broiler Cockcrels Four replicates of five hirds each Due to coccidiosis.

TABLE IV Efficacy of A204l Derivatives Against '0 E. Brunem' in Broiler Cockerels Reduction 7c Mor- 7: Average A204l in tal- Weight Lesion Lesion Ether Diet ity Gain Score Score Methyl .02 0 83 0 100 .0l 0 74 0 I00 .005 0 70 0.87 n-Propyl .01 0 89 0 100 .005 0 89 0 100 .0025 0 95 0.80

Infected 0 5l 7 0.85 Controls Normal 0 100 Controls Four replicates of five hirds each 'Due to coccidiosis.

TABLE V Efficacy of A204l Derivatives Against a Mixed Infection of E. maxima and E. tenella in Broiler Cockerels Intestinal Lesions maintained on a high-grain ration, the composition of which follows:

69.9571 coarse ground corn 10.007: ground corncobs 8.00% soybean meal (50% protein) 500% alfalfa meal 5.00% molasses 0.60% urea 0.50% dicalcium phosphate 0.50% calcium carbonate 0.30% salt 0.07% vitamins A and D premix* 0.05% vitamin E premix** 0.03% trace mineral premix*** *Containing per pound: 2.000.000 LU. of vitamin A; 227,200 LU. of vitamin D, and 385.7 g 'of soybean feed with l71 oil added *Corn distillers dried grains with solubles. containing dalpha-tocopheryl acetate per pound 20,000 LU. of

/ ***Containing manganous oxide. potassium iodide. cobalt carbonate. copper oxide and zinc sulfate Cecal Lesions Three replicates of five birds each per medicated group; four replicates of five birds each per infected-control group. Due to coccidiosis.

In another aspect, the A2041 derivatives of the present invention improve feed utilization in ruminants which have a developed rumen function. Young ruminants, basically those still unweaned, function as monogastric animals. As young ruminants being to eat solid food, the rumen function begins to develop; and the microbiological population of the rumen being to increase. After the animal has eaten solid feed for a time, its rumen function reaches full development and continues to operate throughout the animals life. Some economically important ruminant animals are cattle, sheep and goats.

The A2041 derivatives of the present invention are typically effective in increasing efficiency of feed utilization when administered to ruminants orally at rates of from about 0.25 to about l2.5 mg/kg/day. Most beneficial results are achieved at rates of from about 0.5 to about 7.4 mg/kg/day. A preferred method of administering the compounds of the present invention is by mixing them with the animals feed; however, they can be administered in other ways, for example, tablets, drenches, boluses, or capsules. Formulation of these various dosage forms can be accomplished by methods well known in the veterinary pharmaceutical art. Each individual dosage unit should contain a compound of this invention in a quantity directly related to the proper daily dose for the animal to be treated.

The ability of the compounds of this invention to increase feed-utilization efficiency in ruminants is illustrated by the following in vitro test:

METHOD A sample of rumen fluid is strained through four layers of cheesecloth, and the filtrate is collected. The particulate matter retained by the cheesecloth is resuspended in enough physiological buffer to return it tothe original volume of the rumen fluid, and this suspension is strained again. The buffer used has the following composition:

I as described by Cheng et al. in J. Dairy Sci. 38,

The two filtrates are combined and allowed to stand until particulate matter separates to the top. The clear layer is separated, diluted with the same buffer (1:1)

and then adjusted to between pH 6.8-7.0. The diluted rumen fluid (10 ml) is placed in a -ml flask with mg of the above-described feed, an additional 5 mg of soybean protein, and the compound to betested. Four replicate flasks are used per treatment.

Two sets of fourc ontrol flasks each are also employed.

A zero-time control and an incubated 16-hour control are used. All test flasks are incubated for 16 hours at TABLE V! Feed-Utilization Efficiency Activity of A204! Derivatives Certain of A204! derivatives are also insecticides and acaricides. For example, the A204! methyl ether and ethyl ether derivatives are active against insects, such as Southern armyworm and housefly, and against mites, such as two-spotted spider mite, when applied at rates as low as 1000 ppm and are also active against mosquito larvae when applied at rates as low as 20 ppm.

The A204! derivatives of the present invention also inhibit the growth of other pathogenic organisms. For example, both the A2041 ethyl ether and methyl ether derivatives inhibit the growth of Bacillus subtilis and Mycobucterium avium at levels as low as 1.25 micrograms per milliliter and anaerobic bacteria at levels as low as 0.5 microgram per milliliter.

The A2041 derivatives of the present invention are less toxic than antibiotic A2041. The acute toxicity in mice of antibiotic A2041, administered orally and expressed as LD iS 10 mg/kg. The acute toxicities in mice of various of the A2041 derivatives, also administered orally and expressed as LD,-, are as follows:

Compound !..D,,,,(mglkg) A204! methyl ether 43 i 8 and 70 z 10 A2041 ethyl ether 1 i 30 A204! n-propyl ether 38 t 6 A204! isopropyl ether 36 A comparison of the effects of A204! n-propyl ether with those of antibiotic A2041 in feeding studies in rats gives further evidence of the advantage of the A204! derivatives. For this test, five rats of each sex were studied for 14 days at each treatment level. The mean changes in body weight and the mean amounts of food ingested were calculated for each group. A comparison of the results of these tests is given in Table V11:

TABLE V11 Rat Feeding Studies Male Female Body Body Level Weight Food Weight Food Com- (ppm) Change (g) (g) Change (g) (g) pound Control +58.2 238 +432 236 A204! 5 +314 224 +202 189 10 29.8 147 25.4 137 A204l- 5 +77.8 281 +340 224 npropyl 10 +452 221 +360 218 ether 20 +666 288 +31.6 229 The following examples are provided to more fully illustrate the preparation of the compounds of the present invention.

EXAMPLE 1 Preparation of A204! Methyl Ether Derivative from A2041 Sodium Salt Antibiotic A2041 sodium salt (20 g) was dissolved in methanol 1.1 and water (500 ml) was added slowly. This solution was adjusted to pH 3.0 by the addition of 6 N hydrochloric acid. The resulting solution was stirred for 1 hour and then was extracted with an equal volume of chloroform. This chloroform extract was evaporated to dryness under vacuum.

The resulting residue (2 g) was dissolved in 10 ml of a benzene-ethyl acetate (7:3) mixture, and this solution was chromatographed on a 2- X 51-cm silica gel column (Woelm), eluting with the same benzene-ethyl acetate solvent mixture. Elution was monitored by thinlayer chromatography. The fractions containing A204! methyl ether derivative were combined and evaporated to dryness under vacuum. A2041 methyl ether derivative (1.4 g) crystallized from methanol-water, mp ll51l7C, [01],, +7500 (c=1, CH O1-1);p1(,,' (66% aqueous dimethylformamide) 7.1

Analysis. Calculated for C d-1 0 (percent):

C, 62.61; H, 9.04; O, 28.35. Found (percent):

C, 63.88; H, 8.97; O, 27.66.

R, values of A2041 methyl ether derivative are reported in Example 6.

EXAMPLE 2 Preparation of A204! Methyl Ether Derivative from A2041 Antibiotic A2041 in the acid form (400 mg) was dissolved in methanol 10 ml), and water (5 ml) was added. After being allowed to stand one hour, the solution was evaporated under vacuum. The resulting residue was chromatographed as described in Example 1, to give A2041 methyl ether derivative.

EXAMPLE 3 Preparation of A204! n-Propyl Ether Derivative Antibiotic A2041 in the acid form (10 g) was dissolved in n-propanol (200 ml). This solution was allowed to stand at room temperature for one week and then was evaporated to dryness in vacuo. The residue thus obtained was a mixture of starting A204! and the desired product.

give 4.15 g. of A-204l n-propyl ether derivative, mp

ll4116C, [a],, 73.08 (c=l, CH Ol-1); pK,,' (66% aqueous dimethylformamide) 7.8.

Analysis. Calculated for C H O (percent):

C, 63.26; H, 9.19; O, 27.55. Found (percent):

C, 63.60; H, 9.74; O, 26.87. v

R; values of A2041 n-propyl ether derivative are reported in Example 6 EXAMPLE 4.

Preparation of A2041 Methyl Thioether Derivative Antibiotic A2041 in the acid form (400 mg) was added to a solution containing acetone (10 ml), methanethiol (100 ml) and p-toluenesulfonic acid (10 Solvent System Y benzenezethyl acetate (4: l provided fractions containi g A2041 n-butyl. ether derivative. These fractions were combined and evaporated under vacuum to dryness;: the residue thus obtained crystallized from acetonitrile-water to give 156 mg of A2041 n-butyl ether derivative. I a

' EXAMPLE 6 Preparation of A2041 Ethyl Ether Derivative A2041 ethyl ether derivative was prepared from antibiotic A2041 and ethanol by the method used in Example 3, crystallized from acetonitrile, mp 1l7120C., [01],, 74.23 (c=1, CH OH); pK,, (66% aqueous dimethylformamide) 8.0.

Analysis. Calculated for C l-1 0 (percent):

c, 62.94; H, 9.11;'0, 27.95. Found (percent):

C, 63.34; H, 9.12; O, 27.21.

The R; values of A2041 ethyl ether, methyl ether, and

n-propyl ether derivatives in various paper and thinlayer chromatographic systems, using Bacillus subtilis ATCC 6633 (pH 6.0) as the bioautograph test organism, are as follows (antibiotic A2041 values given as a reference standard):

, R, Values Paper: I A204l Ethyl Ether Methyl Ether n-Propyl Ether waterzmethanolzacetone (12:3:1)- 0.41 0.35 0.33 0.21

solution is adjusted to pH 10.5 with NI'LOH and then lowered to pH 7.5 with H PO water:methanol:acetone(12:3:1)- 0.50 0.74 0.70 0.77 solution is adjusted to pH 10.5 with NH,OH and then lowered to pH 7.5 with dil. HCI 1% methyl isobutyl ketone, 0.34 0.44 0.56 0.21 0.5% NI-LOH in water v benzene saturated with water 0.49 0.57 0.68 0.53 waterzethanolzacetic acid (70:24:6) 0.61 0.52 0.67 0.59 water with 1% piperidine and 0.71 v 0.57 0.74 0.62 i 2% p-toluenesulfonic acid Thin-Layer-Silica Gel ethyl acetate 0.66 0.66 0.48 0.69 ethyl acetate:benzene(1:1) 0.23 0.41: 0.30 0.51 ethyl acetatezchloroform (2:1) 0.43 0.49 0.38 0.60 Thin Layer-Cellulose: I g f Waterzmethanohacetone (12:3:1)- 0.27 0.53 I 0.67 0.22

solution is adjusted to pH 10.5 with Nl-LOH and then lowered to pH 7.5 with dil. HCl

mg). The resulting solution was allowed to stand at room temperature for 16 hours and then was evaporated to dryness in vacuo. The residue thus obtained was dissolved in a minimal amount of benzene2ethyl acetate (4:1); this solution was applied to a 2- X 40-cm silica gel (Grace 62) column. Elution with benzenezethyl acetate (4:1) provided fractions containing A204l methyl thioether derivative; these fractions were combined and evaporated in vacuo. The residue thus obtained crystallized from acetonitrile-water to give 119 mg of A2041 methyl thioether derivative.

EXAMPLE 5 Preparation of A2041 n-Butyl Ether Derivative Antibiotic A204l in the acid form (500 mg) was dissolved in n-butanol (25 ml); 0.01 N hydrochloric acid (2.5 ml) was added. The resulting solution was allowed to stand at room temperature for 72 hours and then was evaporated to dryness in vacuo. The residue'thus obtained was dissolved in a minimal amount of benzenezcthyl acetate (4:1 this solution was applied to a 2- by 50-cm silica gel (Grace 62) column. Elution with EXAMPLES 7-21 A204l n-pentyl ether derivative, prepared by reaction of antibiotic A2041 and n-pentanol, using the method of Example 4.

A204l methoxycarbonylmethyl ether derivative, prepared by reaction of antibiotic A2041 and methyl glycolate, using the method of Example 4.

A204l hydroxyethyl ether derivative, prepared by reacting antibiotic A204! and ethylene glycol, using the using the method of Example 3, mp l28-l30C.

A2041 ethyl thioether derivative, prepared by reaction of antibiotic A2041 and ethanethiol, using the method of Example 4.

A2041 2,2,2-trichloroethyl ether derivative, prepared by reaction of antibiotic A2041 and 2,2,2- trichloroethanol, using the method of Example 2.

A2041 2,2,2-trifluoroethyl ether derivative, prepared by reaction of antibiotic A2041 and 2,2,2- trifluoroethanol, using the method of Example 2.

A2041 2,3-dihydroxyprop-l-yl ether derivative, prepared by reaction of antibiotic A2041 and glycerol, using the method of Example 4.

A2041 benzyl ether derivative, prepared by reaction of antibiotic A2041 and benzyl alcohol, using the method of Example 4.

A2041 phenyl ether derivative, prepared by reaction pared by reaction of antibiotic A2041 and 4-tert-buty1- benzenethiol, using the method of Example 4.

A2041 3-(m-methoxyphenyl)prop-l-yl ether derivative, prepared by reaction of antibiotic A2041 and B-(m-methoxyphenyl)propanol, using the method of Example 4.

A2041 4-n-butoxyphenyl ether derivative, prepared by reaction of antibiotic A2041 and 4-n-butoxyphenol, using the method of Example 4.

A2041 4-hydroxybenzyl ether derivative, prepared by reaction of antibiotic A2041 and 4-hydroxybenzyl alcohol, using the method of Example 4.

A204l S-chloropent-l-yl ether derivative, prepared by reaction of antibiotic A2041 and 5-chloro-lpentanol, using the method of Example 4.

1 claim:

1. The A2041 derivative of the formula:

of antibiotic A2041 and phenol, using the method of Example 4.

A2041 tolyl thioether derivative, prepared by reaction of antibiotic A2041 and thiocresol, using the method of Example 4.

A2041 3-phenylprop-l-yl ether derivative, prepared by reaction of antibiotic A2041 and 3-phenyl-lpropanol, using the method of Example 4.

A2041 2-tert-butyl-o-methylphenyl ether derivative, prepared by reaction of antibiotic A2041 and 2-tertbutyl-o-methylphenol, using the method of Example 4.

A2041 4-tert-butylphenyl thioether derivative, prewherein:

Y represents 0; and R represents C,C -alky],

and the physiologically-acceptable cationic salts thereof.

2. The A2041 derivative of claim 1 wherein R is methyl.

3. The A2041 derivative of claim 1 wherein R is ethyl. 4. The A2041 derivative of claim 1 wherein R is npropyl. 

1. THE A2041 DERIVATIVE OF THE FORMULA:
 2. The A204I derivative of claim 1 wherein R is methyl.
 3. The A204I derivative of claim 1 wherein R is ethyl.
 4. The A204I derivative of claim 1 wherein R is n-propyl. 